Our initial grant application proposed to synthesize and evaluate novel CB1 ligands for the treatment of addiction to methamphetamine (METH). The overall research goal was to identify CB1 antagonists and CB1 agonists with low in vivo efficacy and included design and synthesis of: 1) novel CB1 antagonists with neutral or inverse agonist efficacy including biarylpyrazole and biarylimidazole analogs; and 2) CB1 ligands varying in agonist efficacy including i) aminoalkylindole (AAI) ligands based on our CB1 agonist prototype AM5983 and ii) biarylether sulfonate (BAS) analogs based on the partial agonist BAY59-3074. To date, we have fulfilled the goals of our initial proposal including synthesis and evaluation of novel CB1 ligands from the specified chemical classes as well as in vitro and in vivo evaluation of the most promising compounds. This work has led to the discovery of a new family of CB1 neutral antagonists as well as CB1 agonists with different efficacies. In the search for druggable CB1 partial agonists we also have expanded our scope to include two novel classes of cannabinergic ligands that provided us with promising initial results. During the next five year period we intend to advance our current work so as to move our advanced candidate medications for stimulant addiction into the preclinical pre-IND stage. It is important to note that our successful pre-IND candidate and backup compounds also will be eligible for testing as potentially useful medications for nicotine, as well as methamphetamine, addiction. To accomplish our goals, we will design, synthesize, and characterize later generation neutral CB1 antagonists with improved overall pharmacological profiles as potential back-ups for our current class of CB1 neutral antagonists. The major effort of optimization will be towards obtaining efficacious and safe IND candidates. This will encompass both pyrazole and imidazole analogs with good brain penetration and enhanced oral bioavailability. We also will develop novel CB1 selective agonists with low agonist efficacy. We will continue to optimize the two currently-studied classes of CB1 agonists (AAI, BAS) for CB1/CB2 selectivity, low CB1 efficacy and druggability profiles and, as well, extend the available SAR to identify druggable candidates from two additional cannabinergic classes (adamantyl cannabinoids and (+)-cannabidiol analogs with absolute stereochemistry opposite of the naturally occurring (-)-cannabidiol. The most promising compounds from these synthesis programs will be further studied to determine their a) in vitro efficacy and b) relative ability to cross the blood brain barrier. Based on these data, novel ligands will be selected for in vivo studies to determine a) behavioral profiles of action using CB1-mediated hypothermia and operant assays especially designed to identify low-efficacy agonists in rats and monkeys and, for the most advantageous candidates, b) attenuation of methamphetamine's relapse-related effects using drug discrimination and i.v. self-administration procedures in monkeys.